Cancer immunotherapeutics are aimed by and large at modulating the response of the immune system to induce or enhance killing of tumor cells. This approach utilizes using various immunomodulators including monoclonal antibodies that selectively bind to a specific determinant on T cells, thereby either initiating an activation pathway or inducing an inhibitory effect.
The main tumor-cell-killing effector cells are cytotoxic T lymphocytes, though accumulating evidence suggests that T-helper cells are also essential for priming the immune system against tumors. T-helper cells activate nonspecific immune effector mechanisms in the course of tumor destruction by secreting appropriate cytokines such as interferon-gamma among others.
BAT (also referred to as mBAT-1 or BAT-1) is a monoclonal antibody that was generated against a membrane preparation of a Burkitt lymphoma cell line (Daudi) and exhibits anti-tumor and immunostimulatory effects towards various types of tumors (Hardy et al., 2001, Int. J. Oncol. 19:897). BAT monoclonal antibody was disclosed in U.S. Pat. No. 5,897,862 to Hardy et al., which is incorporated in its entirety by reference, as is fully set forth herein. The polynucleotide and amino-acid sequences of murine BAT are disclosed in WO 00/58363, to Hardy et al., and U.S. Pat. No. 7,695,715, both publications incorporated herein by reference.
The BAT anti-tumor activity was studied in SCID (severe combined immunodeficiency disease) mice, beige mice that are deficient in NK cells and nude mice that are deficient in T cells (Hardy, B., 1997, Proc. Natl. Acad. Sci. USA 94:5756). All mice were injected i.v. with murine B16 melanoma cells and subsequently developed tumors in the lungs. BAT exerted an anti-tumor effect in SCID mice that were engrafted with either murine or human lymphocytes. In the athymic nude mice and the beige mice BAT exerted an anti-tumor activity, though this activity was less effective as compared to the anti-tumor activity of BAT in the wild-type mice.
The immunomodulatory effect of BAT was studied in vitro as well. Murine BAT activated CD4+ T cells and induced the secretion of IFN-γ from these cells (Hardy et al., 2000, Int. Immunol. 12:1623 and Quaglino E. et al., 2005, Vaccine 9:23(25):3280-7, respectively). In addition. Hardy et al. showed that BAT triggers the proliferation of T cells and increases their cytolytic activity (Hardy, B. et al., 1997, Hum. Antibodies, 8:95).
U.S. Pat. No. 7,332,582 discloses humanized monoclonal antibodies termed hBAT-1, comprising the complementarity-determining regions (CDRs) of murine monoclonal antibody BAT-1, e.g. the antibody having the nonproprietary name pidilizumab.
U.S. Patent Application Publication No. 2009/0123413 relates to the use of the immunostimulatory pidilizumab monoclonal antibody for treatment of a variety of immuno-deficiency related diseases and disorders and malfunction or incompetence of the immune system.
U.S. Pat. No. 8,747,847 relates to methods for inhibiting tumor growth, increasing survival of a subject having a tumor and inducing protection against tumor recurrence in a mammal, the methods comprise administering a humanized monoclonal antibody comprising CDR regions derived from the mBAT-1 murine monoclonal antibody, e.g. pidilizumab, in combination with at least one chemotherapeutic agent. U.S. Pat. No. 8,686,119 provides modified antibodies or fragments thereof having specific amino acid modifications compared to hBAT-1, humanized monoclonal immunomodulatory BAT-1 antibody (e.g. pidilizumab). Further provided were pharmaceutical compositions comprising said modified antibodies, and use thereof for the treatment of a variety of indications, particularly cancer and immunodeficiency disorders.
Autologous hematopoietic stem cell transplantation (ASCT or AHSCT) or high-dose autologous stem cell transplantation (HD-ASCT) have been shown to be the best available treatment in patients who have relapsed from non-Hodgkin's lymphoma (NHL) after conventional chemotherapy, but who remained chemotherapy-sensitive (Philip T. et al. New Engl J Med, 1995; 333: 1540-1545). ASCT is usually administered following an additional chemotherapeutic treatment, also termed “salvage chemotherapy”. ASCT is also a preferable treatment in Hodgkin's lymphoma (Hodgkin's disease, HD) patients (Sureda A. et al. J Clin Oncol. 2001 Mar. 1; 19(5):1395-404). Patients for which ASCT is not recommended may undergo other stem cell transplantation procedures including allogeneic stem cell transplantation.
Metabolic imaging allows the recognition of an active tumor mass by identifying regions exhibiting increased metabolic activity. Metabolic imaging methods using (67)gallium, known as Ga-scan or Ga imaging, or (18)fluorodeoxyglucose (FDG), known as PET scan. PET imaging or FDG-PET, have often been employed for patients with Hodgkin's disease and non-Hodgkin lymphoma (Coiffier B., Curr Oncol Rep. 2001 May; 3(3):266-70).
Interestingly, it was demonstrated that FDG-PET imaging performed after salvage chemotherapy and prior to stem cell transplantation is predictive of the treatment outcome of NHL patients treated by high-dose chemotherapy and autologous stem cell transplantation (Cremerius et al. Bone Marrow Transplantation 2002(30), 103-111; Alousi A M et al. Br J Haematol. 2008 September; 142(5):786-92). Similar results were obtained in a study which investigated the predictive value of FDG-PET imaging prior to treatment with high dose chemotherapy and stem cell transplantation in 16 patients, including 10 NHL patients and six Hodgkin's disease patients (Becherer et al. Leukemia 2002; 16: 260-267).
Poulou et al. performed a meta-analysis of published trials involving FDG-PET scans obtained prior to ASCT in lymphoma patients (Poulou et al. Eur J Nucl Med Mol Imaging. 2010 January; 37(1):156-62). The meta-analysis found that FDG-PET scans following second-line chemotherapy (also termed “salvage chemotherapy”) and before ASCT have significant prognostic value with respect to progression-free survival (PFS) and overall survival (OS) rates. The study confirmed that the survival rates of malignant lymphoma patients which had a positive pre-transplant PET scan result are significantly worse than those of patients who had a negative PET result. Although there was a clinical heterogeneity between the lymphoma types in the different studies analyzed by Poulou el al, no statistical heterogeneity was found between the studies and thus a positive pre-transplant FDG PET scan was concluded to be a uniform measure of progression and survival rates following ASCT in lymphoma patients.
Recently, Armand et al. reported the progression-free and overall survival rates of 105 patients with diffuse large B-cell lymphoma (DLBCL) who underwent autologous stem-cell transplantation in the last decade. Among this cohort, the survival rate of 46 patients who were chemosensitive but had a positive FDG-PET scan after salvage chemotherapy was examined. In this group, the 18-month post-transplant progression free survival PFS was 52% (90% CI, 0.39 to 0.63) (Armand P. et al., Br J Haematol., 160:608-617, 2013).
A recent study in DLBCL patients assessed the predictive value of PET imaging or Ga imaging (PET/G) on the survival rates following ASCT. The study found that evidence of disease on PET/G scanning prior to transplantation is associated with an increased risk for relapse after ASCT (Alousi A M et al., Br J Haematol 142:786-792, 2008).
An international Phase II Trial (registered at clinicaltrials.gov under NCT-00532259) was designed to test the safety and effectiveness of the monoclonal antibody pidilizumab in patients with several types of non-Hodgkin lymphomas (e.g., diffuse large B cell lymphoma, transformed follicular lymphoma, diffuse mixed cell lymphoma and mediastinal large cell lymphoma), who received autologous peripheral blood stem cell transplantation (Armand et al., J. Clin. Oncol., 31(33):4199-206, 2013).
There is an unmet need for methods for increasing progression free survival as well as overall survival of cancer patients, including but not limited to lymphoma patients, following stem cell transplantation. In particular, in the rituximab era, the prognosis of patients with relapsed or refractory disease is poor. New therapies are therefore needed to increase the success rate of AHSCT, particularly in patients classified as positive for active disease prior to transplantation by means of metabolic imaging (e.g., PET) which are known to have a poor survival rate.